The survival, growth, maintenance and function of certain classes of nerve cells during development are believed to depend on nerve growth factors. A molecule that functions as a nerve growth factor is ependymin.
Ependymin is a glycoprotein that is synthesized in the brain by specific cells which secrete and maintain a steady-state concentration of the protein in the brain extracellular (ECF) and cerebrospinal (CSF) fluids. Ependymin comprises dimers of two polypeptide chains (alpha, M.W. 37,000 and beta, M.W. 31,000) linked by disulfide bonds. These are converted to the gamma-chain (M.W. 26,000) in ECF. The amino acid sequences of the alpha, beta and gamma chains are substantially identical. Ependymins are initially released into the extracellular spaces of the brain as mixtures of .alpha..beta. dimers (M.W. 68,000) which become converted to .beta..gamma. (M.W. 58,000) and .gamma..sub.2 (M.W. 53,000) dimers. Shashoua, V. E., J.Physiol. (Paris) 83:232-329 (1989). The mode by which ependymin functions as a nerve growth promoter is not known. Ependymin has been implicated in the consolidation process of long-term memory formation. V. E. Shashoua, Cell. Molec. Neurobiol., 5:183-207 (1985).
For nerve growth factors to be therapeutically useful, they must be delivered to an active site in the body. This requirement is beset with several difficulties. First, although many nerve growth factors are peptides, P. L. McGeer et al., "Molecular Neurobiology of the Mammalian Brain", 2nd Edition, Plenum Press, 1987, the particular amino acid sequences responsible for their nerve growth-promoting properties are either unknown or are poorly characterized.
Second, ingestion of a drug containing a nerve growth factor often is not possible because many drugs will not survive the environment of the stomach. Thus, easy and safe self-administration of many drugs is not available. A drug, of course, can be injected directly into the bloodstream of the patient. However, because some drugs do not survive for very long in the bloodstream, frequent injections may be necessary, at great inconvenience to the patient. The inability of a drug to survive in the bloodstream can also be overcome in certain instances by increasing the dosage. Unfortunately, increasing the dosage can result in undesireable side effects.
The delivery of a nerve growth factor such as ependymin into the central nervous system (CNS) via the bloodstream involves an additional and extraordinary obstacle; the nerve growth factor must be capable of crossing the blood-brain barrier. The blood-brain barrier may be regarded as a biological exclusion barrier involving both passive and active transport, the barrier controlling the exchange of materials between the plasma and the central nervous system. Many drug substances, including ependymin, are unable to pass through this barrier in efficacious amounts, or at all. Therefore, attempts to increase the level of ependymin in the central nervous system by introducing it into the bloodstream are not successful because it does not cross the blood-brain barrier. Therefore, it would be useful to develop molecules having the same, or greater, activity as ependymin that could be adapted easily to be introduced into the central nervous system.